Introduction: Stroke-induced brain edema is a life-threatening complication for patient. Pre-clinical studies have shown that comorbidities such as diabetes (DB) and hyperlipidemia (HL) are associated with the enhanced edema, however the underlying mechanism is not clear. Vascular endothelial growth factor (VEGF)-A has a major role in angiogenesis and vascular permeability by binding with the VEGF receptor 2 (VEGFR-2).
Hypothesis: We therefore hypothesized that VEGF signaling contributes to comorbidity-enhanced edema in ischemic stroke.
Methods: DB was induced in male C57BL/6 mice by feeding a high fat diet for 8 weeks with or without streptozotocin administration. HL was generated in male ApoE knock-out mice by feeding a high fat diet for 8 weeks. The mice were then subjected to 30 min transient middle cerebral artery occlusion and brain infarct and edema size were determined at 3 days post-stroke. Gene or protein expressions of VEGF-A, VEGFR-2, and the downstream pathway (phospho(p)-Akt and endothelial specific molecule (Esm)-1) were determined in the brain following stroke.
Results: DB and HL mice displayed hyperglycemia and hyperlipidemia. Following stroke, DB and HL mice exhibited larger infarct and edema, and increased VEGF-A and VEGFR-2 expression compared to normal mice. The increase was accompanied by increased pAkt and Esm1 expression. We also found that the VEGFR-2 gene was positively correlated with the severity of edema in both comorbid conditions but not in normal condition (NC) (Fig. A and B).
Conclusion: The results demonstrate that the VEGF signaling may underlie for comorbidity-enhanced brain edema in stroke. A treatment strategy aimed at reducing edema by targeting VEGF signaling is suggested for stroke patients with the comorbidities.